[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2007124545A1 - Integrase inhibitors - 2 - Google Patents

Integrase inhibitors - 2 Download PDF

Info

Publication number
WO2007124545A1
WO2007124545A1 PCT/AU2007/000560 AU2007000560W WO2007124545A1 WO 2007124545 A1 WO2007124545 A1 WO 2007124545A1 AU 2007000560 W AU2007000560 W AU 2007000560W WO 2007124545 A1 WO2007124545 A1 WO 2007124545A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
cyano
hydrogen
group
pyridin
Prior art date
Application number
PCT/AU2007/000560
Other languages
French (fr)
Inventor
Ian Crosby
Neil Choi
John Joseph Deadman
William Issa
Eric Dale Jones
Katherine Macfarlane
David Ian Rhodes
Original Assignee
Avexa Limited
Monash University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2006902228A external-priority patent/AU2006902228A0/en
Application filed by Avexa Limited, Monash University filed Critical Avexa Limited
Publication of WO2007124545A1 publication Critical patent/WO2007124545A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel pyridine-based compounds for the treatment of viral infections, particularly HIV infections.
  • HIV human immunodeficiency virus
  • a feature of retrovirus replication includes the reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. These steps are required for HIV replication and are mediated by the virus encoded enzymes, reverse transcriptase and integrase respectively.
  • HIV infection follows a path of the virus particle binding to cell surface receptors and co- receptors resulting in fusion of the virus particle with the cell.
  • the contents of the virus are released into the cytoplasm where reverse transcription of the HIV genome occurs.
  • a double stranded proviral DNA copy is produced.
  • the proviral DNA is transported to the nucleus in a complex known as the pre integration complex (PIC) which contains integrase and other viral and possibly cellular proteins.
  • PIC pre integration complex
  • Once inside the nucleus the proviral DNA is integrated into the host cell genome via the action of integrase. Once integrated, transcription and translation of the viral genome can occur resulting in the production of viral proteins and a new viral RNA genome.
  • the integration of the proviral genome into the host cell genome requires the action of an integrase which carries out this process in at least three steps, possibly four.
  • the first step involves the assembly of the viral genome into a stable nucleoprotein complex, secondly, processing of two nucleotides from the 3' termini of the genome to give staggered ends with free 3' OH residues and thirdly the transfer of these ends into the host cell genome.
  • the final step involves the gap filling and repair of the insertion site in the host genome. There is still some conjecture over whether the integrase performs this final step or whether it is carried out by cellular repair enzymes.
  • HIV infection can be treated with a number of inhibitors on the market which target reverse transcriptase, protease or entry into the cell. Treatment of HIV infection with these, or a combination of these, drugs is known to be an effective treatment for AIDS and similar diseases. Shortcomings with the current inhibitors include the rapid emergence and increase incidence of resistance and numerous side effects and hence there is a need for new classes of inhibitors.
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • X is selected from-O-, -S-, -S(O)-, -S(O 2 )-, and -NR 6 -;
  • Y is selected from -O- , and -NR 6 -;
  • each R 6 is independently selected from H and C 1-3 alkyl
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, C 6-1 oaryl, C 6-1 oarylC 1-3 alkyl, heterocyclyl, hetereoaryl, C 1-1O aIlCyI and C 3-1 ocycloalkyl, -NR 7 R 8 , -SCi-Cioalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, -C(O)NR 7 R 8 , -CH 2 NR 7 R 8 , and CO 2 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1-1O aIlCyI, C 6-1O aTyIC 1-S aIlCyI and C 6-1 oaryl;
  • R 5 is selected from the group consisting of hydrogen, C 1-1O aIlCyI, and Ci- t oalkenyl.
  • a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • X is selected from -O-, -S-, -S(O)-, -S(O 2 )-, and -NR 6 -;
  • Y is selected from -0-, and -NR 6 -;
  • each R 6 is independently selected from H and C 1-3 alkyl
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, C 6-1 oaryl, C 6-1 oarylC 1-3 alkyl, heterocyclyl, hetereoaryl, C ⁇ oalkyl and Ca- t ocycloalkyl, -NR 7 R 8 , -SCi-Cioalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, -C(O)NR 7 R 8 , -CH 2 NR 7 Rs, and CO 2 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1-1O aIkVl, C ⁇ oarylCi-salkyl and C 6-1 oaryl;
  • R 5 is selected from the group consisting of hydrogen, C 1-1O aIkVl, and C 2-1 oalkenyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the third aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the present invention display anti- viral activity.
  • the present inventors have found that the compounds inhibit HIV replication in infected cells and have also shown that the compounds inhibit the activity of HIV integrase in vitro.
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • X is selected from -O-, -S-, -S(O)-, -S(O 2 )-, and -NR 6 -;
  • Y is selected from -O- , and -NR 6 -;
  • each R 6 is independently selected from H and C 1-3 alkyl
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, C 6-1 oaryl, C 6-1 oarylC 1-3 alkyl, heterocyclyl, hetereoaryl, C 1-10 alkyl and C 3-10 cycloalkyl, -NR 7 R 8 , -SCi-Cioalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, -C(O)NR 7 R 8 , -CH 2 NR 7 R 8 , and CO 2 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1-1O aIlCyI, C 6-1 oarylC 1-3 alkyl and C 6-1 oaryl; and
  • R 5 is selected from the group consisting of hydrogen, Ci.ioalkyl, and C 2-1 oalkenyl.
  • R 1 is selected from C ⁇ -ioaryl and heteroaryl.
  • R 2 is selected from C 6-1 oaryl, heteroaryl, heterocyclyl and C 3 - 6 cycloalkyl.
  • R 3 is selected from hydrogen and cyano, more preferably cyano.
  • R 4 is C 6 aryl.
  • R 5 is selected from hydrogen and C 2-3 alkenyl, more preferably R 5 is allyl.
  • Preferred heteroaryl substituents are selected from the group consisting of thiophenyl, furanyl, benzofuranyl, and imidazolyl.
  • Preferred heterocyclyl substituents are selected from the group consisting of 2,2-dimethyl-l,3- dioxalane and tetrahydrofuran.
  • the compound of formula I is selected from the group consisting of:
  • a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the viral infection of the first and second aspects is a HIV infection.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • X is selected from -O-, -S-, -S(O)-, -S(O 2 )-, and -NR 6 -;
  • Y is selected from -0-, and -NR 6 -;
  • each R 6 is independently selected from H and C 1-3 alkyl;
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, C 6-1 oaryl, C ⁇ -ioarylCi-salkyl, heterocyclyl, hetereoaryl, C 1-lo alkyl and C 3-10 cycloalkyl, -NR 7 Rs, -SCi-Cioalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, -C(O)NR 7 R 8 , -CH 2 NR 7 R 8 , and CO 2 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C t -ioalkyl, C 6-1 oarylC 1-3 alkyl and C 6-1 oaryl;
  • R 5 is selected from the group consisting of hydrogen, Ci-ioalkyl, and C 2-1 oalkenyl.
  • R 1 is selected from C 6-1 oaryl and heteroaryl.
  • R 2 is selected from C 6-1 oaryl, heteroaryl, heterocyclyl and C 3 - 6 cycloalkyl.
  • R 3 is selected from hydrogen and cyano.
  • R 4 is C 6 aryl.
  • R 5 is selected from hydrogen and C 2-3 alkenyl, more preferably R 5 is allyl.
  • Preferred heteroaryl substituents are selected from the group consisting of thiophenyl, furanyl, benzofuranyl, and imidazolyl.
  • Preferred heterocyclyl substituents are selected from the group consisting of 2,2-dimethyl-l,3- dioxalane and tetrahydrofuran.
  • the compound of formula I is selected from the group consisting of:
  • halo or halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
  • alkyl either used alone or in compound terms such as NH(alkyl) or N(alkyl) 2 , refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate.
  • suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-metliylpentyl.
  • alkenyl refers to straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to ethenyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and hexenyl.
  • alkynyl refers to straight chain or branched hydrocarbon groups containing one or more triple bonds. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexenyl.
  • cycloalkyl refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to a C 6 -C 1O aromatic hydrocarbon group, for example phenyl or naphthyl.
  • arylalkyl includes, for example, benzyl.
  • heterocycle when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3-6 ,wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include, O, N and S.. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc.
  • heteroaryl includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S.
  • Suitable examples of heteroaryl groups include tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc.
  • the heteroaromatic ring may be fused to a 5- or 6- aromatic or heteroaromatic ring to form a bicyclic aromatic system eg benzofuran.
  • Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of C!-C 3 alkyl, C 3 -C 6 cycloalkyl, C 6 aryl, heterocyclyl, heteroaryl, C r C 3 alkylOH, alkylaryl, OH, OQ-Csalkyl, halo, CN, NO 2 , CO 2 H,
  • an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl.
  • Each optional substituent may also be optionally substituted.
  • optional substituents also include suitable nitrogen protecting groups (see “Protective Groups in Organic Synthesis” Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivative may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • This invention also encompasses prodrugs of compounds of formula I.
  • This invention also encompasses methods of treating or preventing disorders in a subject that can be treated or prevented by the inhibition of AIDS and other disorders that can be treated by inhibition of the integrase enzyme by administering prodrugs of compounds of the formula (I).
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
  • the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the present invention provides pharmaceutical a composition comprising a compound according to the third aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • parenterally such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • compositions include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
  • effective amount means the amount of the subject composition that will elicit the reduction in viral load or inhibition of viral replication that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment does not necessarily mean that the viral infection is completely cured.
  • treatment encompasses any level of reduction of the viral load and/or inhibition of replication in the subject being treated.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous formic acid Gradient: (linear gradient curve 6)
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Aqueous sodium hydroxide (2.0 M, 30 mL) was added dropwise to a solution of 2-acetyl thiophene (1Og, 8.65 mL, 79.3 mmol) and 2-furan-carboxaldehyde (6.92 g, 72.0 mmol) in ethanol (50 mL). After stirring overnight at room temperature the mixture was diluted by addition of (500 mL) and extracted with ethyl acetate (250 mL). The organic phase was dried (Na 2 SO 4 ), filtered and allowed to stand overnight at 0 0 C.
  • reaction mixture was diluted with ethyl acetate (20 mL) and the combined organics were washed with water (3 x 2OmL) and dried (MgSO 4 ) to afford a tan solid which was further purified by column chromatography (Si, 50% ethyl aetate/hexane/l%acetic acid), yielding 2-[3-cyano-4-(2-furyl)-6-(2-thienyl)-2-pyridinyl]oxy-2-phenylacetic acid as a tan solid (84 mg, 91%).
  • Digoxigenin (DIG; 5'-ACTGCTAGAGATTTTCCACACTGACTAAAAGGGTC-DIG-S') or biotin (5'-BiO-GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT-S') so that each substrate has either a DIG or Bio tag on opposite strands. Reactions are carried out for 2hrs at 37°C, products generated as a result of 3'processing and strand transfer activity are bound to streptavidin plates and detected with using anti-DIG-alkaline phosphatase conjugate and p- nitro phenyl phosphate substrate.
  • the strand transfer specific assay is of similar format to that of the 3'processing/strand transfer combined assay except that it uses a biotinylated substrate that represents a pre- processed LTR end (5'-BiO-GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCA-S').
  • Cells are seeded into 96 well microtitre plates at 50,000 cells per 50ul per well in RF- 10 containing 2 ⁇ g/ mL polybrene (RF- 10/2). Compounds are prepared to 4 x final concentration in RF-10/2, and 30 ⁇ l added to cells. Virus (40 ⁇ l in RF-10/2 containing 1600 pfu) is added to each well or 40 ⁇ l RF-10/2 for negative controls and for assaying compound cytotoxicity.
  • IC 5 0 (3'-ST) represents the assay results for the 3 'processing/strand transfer combined assay
  • Table 5 depicts the "scoring system" used in the assays.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof. Compounds of formula (I) are also provided.

Description

lntegrase Inhibitors - 2
FIELD OF THE INVENTION
The present invention relates to novel pyridine-based compounds for the treatment of viral infections, particularly HIV infections.
BACKGROUND OF THE INVENTION
The retrovirus designated "human immunodeficiency virus" or "HIV" is the etiological agent of a complex disease that progressively destroys the immune system. This disease is known as acquired immune deficiency syndrome or AIDS. As at December 2004, an estimated 40 million people have been infected with HIV world wide and over 3 million deaths are occurring annually.
A feature of retrovirus replication includes the reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. These steps are required for HIV replication and are mediated by the virus encoded enzymes, reverse transcriptase and integrase respectively.
HIV infection follows a path of the virus particle binding to cell surface receptors and co- receptors resulting in fusion of the virus particle with the cell. The contents of the virus are released into the cytoplasm where reverse transcription of the HIV genome occurs. Through a series of steps a double stranded proviral DNA copy is produced. The proviral DNA is transported to the nucleus in a complex known as the pre integration complex (PIC) which contains integrase and other viral and possibly cellular proteins. Once inside the nucleus the proviral DNA is integrated into the host cell genome via the action of integrase. Once integrated, transcription and translation of the viral genome can occur resulting in the production of viral proteins and a new viral RNA genome. These proteins and genome assemble at the cell surface and, depending on cell type, possibly other intracellular membranous compartments. Assembled particles then bud out from the cell and during, or soon after, this process mature into infectious HIV particles through the action of the viral protease. The integration of the proviral genome into the host cell genome requires the action of an integrase which carries out this process in at least three steps, possibly four. The first step involves the assembly of the viral genome into a stable nucleoprotein complex, secondly, processing of two nucleotides from the 3' termini of the genome to give staggered ends with free 3' OH residues and thirdly the transfer of these ends into the host cell genome. The final step involves the gap filling and repair of the insertion site in the host genome. There is still some conjecture over whether the integrase performs this final step or whether it is carried out by cellular repair enzymes.
Currently HIV infection can be treated with a number of inhibitors on the market which target reverse transcriptase, protease or entry into the cell. Treatment of HIV infection with these, or a combination of these, drugs is known to be an effective treatment for AIDS and similar diseases. Shortcomings with the current inhibitors include the rapid emergence and increase incidence of resistance and numerous side effects and hence there is a need for new classes of inhibitors.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000004_0001
X is selected from-O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -O- , and -NR6-;
each R6 is independently selected from H and C1-3alkyl;
R1, R2 and R4 are each independently selected from the group consisting of hydrogen, C6-1oaryl, C6-1oarylC1-3alkyl, heterocyclyl, hetereoaryl, C1-1OaIlCyI and C3-1ocycloalkyl, -NR7R8, -SCi-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, and CO2R9;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-1OaIlCyI, C6-1OaTyIC1-SaIlCyI and C6-1oaryl; and
R5 is selected from the group consisting of hydrogen, C1-1OaIlCyI, and Ci-toalkenyl.
In a second aspect, there is provided the use of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject. In a third aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000005_0001
X is selected from -O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -0-, and -NR6-;
each R6 is independently selected from H and C1-3alkyl;
R1, R2 and R4 are each independently selected from the group consisting of hydrogen, C6-1oaryl, C6-1oarylC1-3alkyl, heterocyclyl, hetereoaryl, C^oalkyl and Ca-tocycloalkyl, -NR7R8, -SCi-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7Rs, and CO2R9;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-1OaIkVl, C^oarylCi-salkyl and C6-1oaryl; and
R5 is selected from the group consisting of hydrogen, C1-1OaIkVl, and C2-1oalkenyl.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound according to the third aspect and a pharmaceutically acceptable carrier, diluent or excipient. DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention display anti- viral activity. The present inventors have found that the compounds inhibit HIV replication in infected cells and have also shown that the compounds inhibit the activity of HIV integrase in vitro.
Accordingly, in a first aspect, the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000006_0001
X is selected from -O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -O- , and -NR6-;
each R6 is independently selected from H and C1-3alkyl;
R1, R2 and R4 are each independently selected from the group consisting of hydrogen, C6-1oaryl, C6-1oarylC1-3alkyl, heterocyclyl, hetereoaryl, C1-10alkyl and C3-10cycloalkyl, -NR7R8, -SCi-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, and CO2R9; R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-1OaIlCyI, C6-1oarylC1-3alkyl and C6-1oaryl; and
R5 is selected from the group consisting of hydrogen, Ci.ioalkyl, and C2-1oalkenyl.
Preferably, R1 is selected from Cβ-ioaryl and heteroaryl.
Preferably, R2 is selected from C6-1oaryl, heteroaryl, heterocyclyl and C3-6cycloalkyl.
Preferably, R3 is selected from hydrogen and cyano, more preferably cyano.
Preferably R4 is C6aryl.
Preferably, R5 is selected from hydrogen and C2-3alkenyl, more preferably R5 is allyl.
Preferred heteroaryl substituents are selected from the group consisting of thiophenyl, furanyl, benzofuranyl, and imidazolyl.
Preferred heterocyclyl substituents are selected from the group consisting of 2,2-dimethyl-l,3- dioxalane and tetrahydrofuran.
Preferably, the compound of formula I is selected from the group consisting of:
Figure imgf000007_0001
Figure imgf000008_0001
In a second aspect, there is provided the use of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
Preferably, the viral infection of the first and second aspects is a HIV infection.
In a third aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000008_0002
X is selected from -O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -0-, and -NR6-;
each R6 is independently selected from H and C1-3alkyl; R1, R2 and R4 are each independently selected from the group consisting of hydrogen, C6-1oaryl, Cβ-ioarylCi-salkyl, heterocyclyl, hetereoaryl, C1-loalkyl and C3-10cycloalkyl, -NR7Rs, -SCi-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, and CO2R9;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, Ct-ioalkyl, C6-1oarylC1-3alkyl and C6-1oaryl; and
R5 is selected from the group consisting of hydrogen, Ci-ioalkyl, and C2-1oalkenyl.
Preferably, R1 is selected from C6-1oaryl and heteroaryl.
Preferably, R2 is selected from C6-1oaryl, heteroaryl, heterocyclyl and C3-6cycloalkyl.
Preferably, R3 is selected from hydrogen and cyano.
Preferably R4 is C6aryl.
Preferably, R5 is selected from hydrogen and C2-3alkenyl, more preferably R5 is allyl.
Preferred heteroaryl substituents are selected from the group consisting of thiophenyl, furanyl, benzofuranyl, and imidazolyl.
Preferred heterocyclyl substituents are selected from the group consisting of 2,2-dimethyl-l,3- dioxalane and tetrahydrofuran.
Preferably, the compound of formula I is selected from the group consisting of:
Figure imgf000010_0001
As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
As used herein, the term "alkyl" either used alone or in compound terms such as NH(alkyl) or N(alkyl)2, refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate. For example, suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-metliylpentyl.
As used herein, the term "alkenyl" refers to straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to ethenyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and hexenyl. The term "alkynyl" as used herein, refers to straight chain or branched hydrocarbon groups containing one or more triple bonds. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexenyl.
The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aryl" as used herein, refers to a C6-C1O aromatic hydrocarbon group, for example phenyl or naphthyl.
The term "arylalkyl" includes, for example, benzyl.
The term "heterocycle" when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C3-6,wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatoms include, O, N and S.. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc.
The term "heteroaryl" includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S. Suitable examples of heteroaryl groups include tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc. The heteroaromatic ring may be fused to a 5- or 6- aromatic or heteroaromatic ring to form a bicyclic aromatic system eg benzofuran.
Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of C!-C3alkyl, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, CrC3alkylOH, alkylaryl, OH, OQ-Csalkyl, halo, CN, NO2, CO2H,
CO2C1-C3alkyl, CONH2, CONH(C1-C3alkyl), CON(C1-C3alkyl)2, trifluoromethyl, NH2, NH(C1-C3alkyl) or N(C1-C3alkyl)2. For example, an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. Each optional substituent may also be optionally substituted.
Examples of optional substituents also include suitable nitrogen protecting groups (see "Protective Groups in Organic Synthesis" Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
The term "pharmaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts" P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley- VCH. Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
This invention also encompasses prodrugs of compounds of formula I. This invention also encompasses methods of treating or preventing disorders in a subject that can be treated or prevented by the inhibition of AIDS and other disorders that can be treated by inhibition of the integrase enzyme by administering prodrugs of compounds of the formula (I). Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
It will also be recognised that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution. In a fourth aspect, the present invention provides pharmaceutical a composition comprising a compound according to the third aspect and a pharmaceutically acceptable carrier, diluent or excipient.
The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). The subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
The term " effective amount" means the amount of the subject composition that will elicit the reduction in viral load or inhibition of viral replication that is being sought by the researcher, veterinarian, medical doctor or other clinician.
As would be understood by those skilled in the art of treating viral infections, and particularly HIV infections, the term "treatment" does not necessarily mean that the viral infection is completely cured. The term "treatment" encompasses any level of reduction of the viral load and/or inhibition of replication in the subject being treated.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
In the treatment or prevention of conditions which require HIV inhibition or HIV integrase enzyme inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non-limiting Examples.
EXAMPLES
Methods
HPLC conditions
All HPLC measurements were performed on a Waters 2690 Alliance System.
Method 1:
Column:
Waters Cl 8 5 uM Symmetry Column (Part # WAT046980) at 30° C, flow rate 0.7 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous formic acid Gradient: (linear gradient curve 6)
10 min 5 min ^ min 5 min 45%A:50%B:5%C *■ 0%A:95%B:5%C >■ 0%A:95%B:5%C >■ 45%A:50%B:5%C »- 45%A:50%B:5%C
Method 2:
Column:
5 Merck C18 Chromolith Column (Part # 1.02129.0001) at 30° C, flow rate 4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
4 min 0.75 min 0.25 min 1 min J Q 95%A:0%B:5%C *- 0%A:95%B:5%C *■ 0%A:95%B:5%C *■ 95%A:0%B:5%C *- 95%A:0%B:5%C
General Scheme 1: Synthesis of core structure
ROUTE 1
ROUTE 2
ROUTE !
Figure imgf000018_0001
LG=halo, OTf Example 1:
Preparation of 4,6-diphenyl-2-thioxo-l,2-dihydro-3-pyridinecarbonitrile (Route 1)
Figure imgf000019_0001
A suspension of cyanothioamide (1.0 g, 9.98 mmol) and dibenzoyl methane (2.24 mg, 9.98 mmol) in dry ethanol (20 mL) was treated with triethylamine (catalytic, 500 μL) then refluxed for 2 hours. Reaction mixture was allowed to cool to room temperature to give a yellow precipitate which was filtered to afford 4,6-diphenyl-2-thioxo-l,2-dihydro-3- pyridinecarbonitrile as a yellow solid (1.02 g, 35%).
1H NMR (300 MHz, D6DMSO) δ 7.11 (IH, s, pyridylH), 7.56 (6H, m, ArH), 7.73 (2H, m, ArH), 7.86 (2H, d, J= 7.2Hz, ArH)
MS (ESI+) m/z 289 (M+l); MS (ESI") m/z 287 (M-I).
Example 2:
Preparation of 4-furan-2-yl-6-thiophen-2-yl-lH-pyridin-2-one and 4-furan-2-yl-6- thiophen-2-yl-2-thioxo-l,2-dihydro-pyridine-3-carbonitrile (Route 2)
2.1 Preparation of (jE')-3-Furan-2-yl-l-thiophen-2-yl-propenone
Figure imgf000019_0002
Aqueous sodium hydroxide (2.0 M, 30 mL) was added dropwise to a solution of 2-acetyl thiophene (1Og, 8.65 mL, 79.3 mmol) and 2-furan-carboxaldehyde (6.92 g, 72.0 mmol) in ethanol (50 mL). After stirring overnight at room temperature the mixture was diluted by addition of (500 mL) and extracted with ethyl acetate (250 mL). The organic phase was dried (Na2SO4), filtered and allowed to stand overnight at 0 0C. The resulting crystals were filtered and washed with hexane (25 mL) and ethanol (10 mL) to afford (E)-3-furan-2-yl-l-thiophen- 2-yl-propenone (10.3 g, 70%).
MS (ESI+) m/z 205 (M+l)
2.2 Preparation of 4-Furan-2-yl-6-thiophen-2-yl-lH-pyridin-2-one
Figure imgf000020_0001
AU fumes from this reaction were vented through a bleach trap:
A steady stream of nitrogen was bubbled through a solution of (E)-3-furan-2-yl-l-thiophen-2- yl-propenone (1.0 g, 4.90 mmol) and 2-cyano-acetamide (453 mg, 5.39 mmol) in DMSO (14 mL). The mixture was cooled to 0 0C before portionwise addition of potassium fert-butoxide (1.65 g, 14.7 mmol) over 20 min. The reaction was warmed to 9O0C and stirred vigorously for 3 hr, still bubbling N2 through. The reaction was cooled to room temperature and slowly transferred into 4M HCl (65 mL) cooled in an ice bath (N.B. liberation of HCN) - keeping the temperature below 2O0C. This solution was stirred until the evolution of gas ceased (approx. 10 min) and filtered, washing the precipitate with water and ethanol to give pure product (983 mg, 83% yield), as a pale brown solid.
1H nmr (300 MHz, CDCl3) δ 7.87, m, IH, Ar-H; 7.84, m, IH, Ar-H; 7.67, dd, 1Η, / 1.2, 5.1 Hz, Ar-H; 7.31, m, 2Η, Ar-H; 7.17, dd, 1Η, J 3.9, 5.1 Hz, Ar-H; 6.68, m, 2Η, Ar-H.
MS (ESf") m/z 244 (M+l). Example 2.3 Preparation of 4-Furan-2-yl-6-thiophen-2-yl-2-thioxo-l,2-dihydro- pyridine-3-carbonitrile
Figure imgf000021_0001
All fumes from this reaction were vented through a bleach trap:
A steady stream of oxygen was bubbled through a solution of (E)-3-furan-2-yl-l-thiophen-2- yl-propenone (1.0 g, 4.90 mmol) and 2-cyano-thioacetamide (540 mg, 5.39 mmol) in DMSO (14 mL). The mixture was cooled to O0C before portionwise addition of potassium tert- butoxide (1.65 g, 14.7 mmol) over 15 min. The reaction was warmed to 5O0C and stirred vigorously, still bubbling O2 through. On completion, the reaction was cooled to room temperature and slowly transferred into 4M HCl (65 mL) cooled in an ice bath (N.B. liberation of HCN) - keeping the temperature below 2O0C. This solution was stirred until the evolution of gas ceased (approx. Vz hr) and filtered, washing the precipitate with water and ethanol. The precipitate was triturated with ether and filtered. The precipitate was triturated with hot glacial acetic acid and filtered on cooling to give pure product (617 mg, 44% yield), as a mixture of monomer and dimer, as an orange solid.
1H nmr (300 MHz, CDCl3) δ 7.70, s, IH, Ar-H; 7.58, m, 1Η, Ar-H; 7.52, dd, 2Η, / 1.2, 3.9 Hz, Ar-H; 7.24, dd, 1Η, / 1.2, 5.1 Hz, Ar-H; 6.91, dd, 1Η, J 3.6, 5.1 Hz, Ar-H; 6.55, dd, 1Η, J 1.8, 3.6 Hz, Ar-H.
MS (ESI+) m/z 567 (M+l) (dimer) Example 3
Preparation of 4-Furan-3-yl-2-oxo-6-thiophen-2-yl-l,2-dihydro-pyridine-3-carbonitrile (Route 3)
Figure imgf000022_0001
3-Furaldehyde (4.8 g, 50.0 mmol), 2-acetylthiophene (8.26 g, 65.5 mmol), ethyl cyanoacetate (5.66 g, 50.0 mmol) and ammonium acetate (37.19 g, 482.5 mmol) were placed into flask and dissolved in absolute ethanol (50 niL). The reaction mixture was stirred at room temperature for 3 d where a yellow solid formed. The reaction was filtered and the yellow solid was washed with water then with ethanol and then suction dried for 1 h to give the product as a fluffy yellow solid, 6.1 g (46%).
1HNMR (D6DMSO, 300 MHz) δ 12.67 (bs, IH, hetero-H), 8.58 (s, IH, H-2 of furan), 8.05 (dd, J 3.9 Hz, 1.2 Hz, IH, H-5 of thiophene), 7.93 (t, / 1.5 Hz, IH, H-4 of furan), 7.88 (app d, /4.5 Hz, IH, H-5 of furan), 7.26 (dd, /4.8 Hz, 3.6 Hz, IH, H-4 of thiophene), 7.22 (dd, / 1.8 Hz, 0.9 Hz, IH, H-3 of thiophene) HPLQnethod 2 98.92%/2.18 min.
MS (ESI+) m/z 291 (M+Na).
Example 4
Preparation of trifluoro-methanesulfonic acid 3-cyano-4-furan-3-yl-6-thiophen-2-yl- pyridin-2-yl ester and 2-bromo-4-furan-2-yl-6-thiophen-2-yl-nicotinonitrile (Route 4)
4.1 Preparation of trifluoro-methanesulfonic acid 3-cyano-4-furan-3-yl-6-thiophen-2- yl-pyridin-2-yl ester
Figure imgf000023_0001
4-Furan-3-yl-2-oxo-6-thioplien-2-yl-l,2-dihydro-pyridine-3-carbonitrile (2.00 g, 7.45 mol) was placed into reaction flask along with dry pyridine (20 mL), stirred at 0 0C under N2. Triflic anhydride (2.5 mL, 14.9 mmol) was added to the suspension reaction dropwise. Some fuming on addition of triflic anhydride. The initial bright yellow colour darkened after a few minutes stirring, the suspension slowly converted to a dark brown solution over a period of 15 min at 0 °C. After which the bath was removed and the reaction mixture was stirred whilst warmed to room temperature and stirred at this temperature for 0.5 h, then evaporated under reduced pressure to give a black/brown solid which was taken up in chloroform. The chloroform solution was loaded onto a silica column and eluted with chloroform. Fractions containing product were collected and evaporated under reduced pressure to give an off-white solid, 1.753 g, 58.7%.
1Hnmr (CDCl3, 300 MHz) δ 8.33 (s, IH, H-2 of furan), 7.83 (d, J 3.6 Hz, IH, H-5 of thiopene), 7.69 (s, IH, pyridyl H). 7.63 (m, 2H, H-4 and H-5 of furan), 7.21 (app t, IH, H-4 of thiophene), 6.97 (s, IH, H-2 of thiophene).
HPLC:method 97.5%/2.86 min MS (ESI+) m/z 401 (M+l).
General Scheme 2: Compound synthesis
Figure imgf000024_0001
Example 5
Preparation of (3-Cyano-4-furan-2-yl-6-thiophen-2-yl-pyridin-2-yloxy)-phenyl-acetic acid allyl ester (Step A)
Figure imgf000024_0002
A solution of 4-(2-furyl)-2-hydroxy-6-(2-thienyl)nicotinonitrile (200 mg, 0.75 mmol) in dry acetone (5 mL) treated with allyl-2-bromo-2-phenylacetate (141 mg, 0.67 mmol), potassium carbonate (206 mg, 1.50 mmol) and sodium iodide (catalytic, 1%). The reaction mixture was refluxed for 4 h under an atmosphere of nitrogen then allowed to cool to room temperature. Following this the reaction mixture was diluted with water (10 mL) and extracted into ethyl acetate (3 x 20 mL). The combined organics were then washed with water (2 x 2OmL), dried (MgSO4) and evaporated under reduced pressure to give a tan solid which was further purified by column chromatography (Silica, 10-20% ethyl acetate/hexane), yielding allyl 2-[3-cyano- 4-(2-furyl)-6-(2-thienyl)-2-pyridinyl]oxy-2-phenylacetate as a tan solid (209 mg, 63%).
1H NMR (300 MHz, CDCl3) δ 4.65 (2H, d, /=5.7Hz, allylH), 5.12-5.24 (2H, m, allylH), 5.78- 5.91 (IH, m, allylH), 6.28 (IH, s, ArCH), 6.62 (IH, dd, J=3.6, 1.8Hz, furylH), 7.14 (IH, dd, /=4.8, 3.9Hz thienylH), 7.40-7.50 (4H, m, furylH/thienylH/2ArH), 7.64-7.66 (2H, m, ArH), 7.73-7.76 (4H, m, furylH/thienylH/2ArH),
MS (ESI+) m/z 443 (M+l); MS (ESI") m/z 441(M-I);
HPLQnethod i 98.6%/9.85min.
By adapting the procedure described in Example 5, the compounds of Table 1 were prepared:
Table 1: Compounds prepared by the procedure of Example 5
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Compound structure Compound name 1EE LC MS
[3-Cyano-4-(4-fluoro- 9.94 471.1 phenyl)-6-thio method 1 (M+l) phen-2-yl-pyridin-2- yloxy]-phenyl-a
Figure imgf000028_0001
cetic acid allyl ester
[3-Cyano-4-(4-nitro- 9.44 498.3 phenyl)-6-thiophen-2-yl- method 1 (M+l) pyridin-2-yloxy] -phenyl- acetic acid allyl ester
[3-Cyano-4-(4-methoxy- Y 9.97 483.3 phenyl)-6-thiophen-2-yl- method 1 (M+l) pyridin-2-yloxy]-phenyl- acetic acid allyl ester
[3-Cyano-4-(4-fluoro- Y 9.82 459 phenyl)-6-thiophen-2-yl- method 1 (M+l) pyridin-2-yloxy] -phenyl- acetic acid ethyl ester
Figure imgf000028_0002
Compound structure Compound name 1H LC MS
(3-Cyano-4-furan-2-yl-6- Y 9.77 431 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid ethyl ester
Figure imgf000029_0001
(3-Cyano-4-furan-2-yl-6- 11.10 439.3 p-tolyl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid ethyl ester
Figure imgf000029_0002
(3-Cyano-4-ethyl-6- 9.71 387.3 phenyl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid ethyl ester
Figure imgf000029_0003
(3-Cyano-6-phenyl-4- Y 10.46 441.3 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid ethyl ester
Figure imgf000029_0004
(3-Cyano-4-isopropyl-6- Y 10.33 401.3 phenyl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid ethyl ester
Figure imgf000029_0005
Compound structure Compound name 1H LC MS
(3 -Cyano-4-thiophen-2- 11.33 455.3 yl-6-ρ-tolyl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid ethyl ester
Figure imgf000030_0001
[3 -Cyano-4-(4-methoxy- 9.88 471 phenyl)-6-thiophen-2-yl- method 1 (M+l) pyridin-2-yloxy] -phenyl- acetic acid ethyl ester
Figure imgf000030_0002
[4-(5-Bromo-lH-indol-3- 11.15 566.3 yl)-3 -cyano-6-phenyl- method 1 (M+l) pyridin-2-yloxy] -phenyl- acetic acid allyl ester
Figure imgf000030_0003
[4-(5-Bromo-lH-indol-3- 11.07 552.2 yl)-3 -cyano-6-phenyl- method 1 (M+l) pyridin-2-yloxy] -phenyl- acetic acid ethyl ester
Figure imgf000030_0004
Compound structure Compound name 1H LC MS
(3-Cyano-4-furan-2-yl-6- 11.13 450.5 p-tolyl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid allyl ester
Figure imgf000031_0001
(3-Cyano-4-ethyl-6- Y 9.85 399.3 phenyl-pyridin-2-yloxy)- method 1 (M+l) phenyl- acetic acid allyl ester
Figure imgf000031_0002
(3-Cyano-4-isopropyl-6- Y 10.41 413.3 phenyl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid allyl ester
Figure imgf000031_0003
(3 -Cyano-6-phenyl-4- Y 10.56 453.2 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid allyl ester
Figure imgf000031_0004
(3 -Cyano-4-thiophen-2~ Y 11.35 467.3 yl-6-p-tolyl-pyridin-2- method 1 (M+l) yloxy)-ρhenyl-acetic acid allyl ester
Figure imgf000031_0005
Compound structure Compound name 1H LC MS
(3-Cyano~4-phenyl-6- 9.94 453.3 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid allyl ester
Figure imgf000032_0001
(3-Cyano-4,6-di- 9.87 459.2 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)-phenyl-acetic acid allyl ester
Figure imgf000032_0002
[6-(4-Bromo-ρhenyl)-3- Y 11.48 533.2 cyano-4-thiophen-2-yl- method 1 (M+l) pyridin-2-yloxy]-phenyl- acetic acid allyl ester
Figure imgf000032_0003
[3-Cyano-4-(4- Y 10.97 490.3 dimethylamino-phenyl)- method 1 (M+l) 6-phenyl-pyridin-2- yloxy]-phenyl-acetic acid allyl ester
Figure imgf000032_0004
[6-(4-Bromo-phenyl)-3- Y 10.93 479.2 cyano-4-ethyl-pyridin-2- method 1 (M+l) yloxy]-phenyl-acetic acid allyl ester
Figure imgf000032_0005
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Compound structure Compound name 1H LC MS
(4-Bromo-phenyl)-(3- Y 11.52 522 cyano-4-furan-2-yl-6- method 1 (M+l) thiophen-2-yl-pyridin-2- yloxy)-acetic acid allyl
Figure imgf000036_0001
ester
(3-Cyano-4-furan-2-yl-6- Y 10.29 461 thiophen-2-yl-pyridin-2- method 1 (M+l) yloxy)~(4-fluoro-phenyl)- acetic acid allyl ester
(4-Bromo-phenyl)-(3- 11.69 538 ?? cyano-4,6-di~thiophen-2- method 1 (M+l) yl-pyridin-2-yloxy)-acetic acid allyl ester
(3-Cyano-4,6-di-furan-2- Y 6.30 427 yl-pyridin-2-yloxy)- method 1 (M+l) phenyl-acetic acid allyl ester
[3-Cyano-4-(5-methyl- Y 11.10 457 furan-2-yl)-6-thiophen-2- method 1 (M+l) yl-pyridin-2-yloxy]- phenyl- acetic acid allyl
Figure imgf000036_0002
ester
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Example 6
Preparation of 2-[(3-Cyano-4,6-diphenyl-2-pyridinyl)sulfanyl]-2-phenylacetic (Step A)
Figure imgf000043_0001
A solution of 4,6-diphenyl-2-thioxo-l,2-dihydro-3-pyridinecarbonitrile (100 mg, 0.35 mmol) in DMF (1 niL) was treated with aqueous (10%) potassium hydroxide (250 μL) and allowed to stir for 10 min. α-bromo phenyl acetic acid (82 mg, 0.38 mmol) was then added and the mixture was allowed to stir overnight. Treatment of the resultant clear solution with IM HCl (ImL) afforded a milky precipitate which was filtered to give 2-[(3-cyano-4,6-diphenyl-2- pyridinyl)sulfanyl]-2-phenylacetic acid as a white solid (124 mg, 84%).
1H NMR (300 MHz, DMSO) δ 5.77 (IH, s, ArCH), 7.11 (IH, s, ArH), 7.38-7.45 (3H, m,
ArH), 7.53-7.59 (8H, m, ArH), 7.74-7.61 (2H, m, ArH), 7.95 (IH, s, ArH), 8.30-8.33 (2H, m, ArH);
By adapting the procedure in Example 6, the compounds of Table 2 were prepared:
Table 2: Compounds prepared by the procedure of Example 6
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0002
Example 7
Preparation of 2-[3-Cyano-4-(2-furyl)-6-(2-thienyl)-2-pyridinyl]oxy-2-phenylacetic acid (Step C)
Figure imgf000049_0001
A solution of (3-cyano-4-furan-2-yl-6-thiophen-2-yl-pyridin-2-yloxy)-phenyl-acetic acid allyl ester (101 mg, 0.23 mmol) in dry THF (3 mL) was treated with tetrakis-triphenylphosphine palladium(O) (catalytic 1%) and allowed to stir at room temperature for 5 min. Sodium borohydride (13 mg, 0.34 mmol) was then added to the yellow solution and the reaction mixture was allowed to stir at room temperature for a further one hour. Following this the excess borohydride was decomposed by treatment with IM HCl (2 mL). After destruction of the borohydride the reaction mixture was diluted with ethyl acetate (20 mL) and the combined organics were washed with water (3 x 2OmL) and dried (MgSO4) to afford a tan solid which was further purified by column chromatography (Si, 50% ethyl aetate/hexane/l%acetic acid), yielding 2-[3-cyano-4-(2-furyl)-6-(2-thienyl)-2-pyridinyl]oxy-2-phenylacetic acid as a tan solid (84 mg, 91%).
1H NMR (300 MHz, CDCl3) δ 6.27 (IH, s, ArCH), 6.65 (IH, dd, 7=3.6, 1.8Hz, furylH), 7.15 (IH, dd, J=4.8, 3.9Hz thienylH), 7.42-7.51 (4H, m, fur ylH/thienylH/2 ArH), 7.66-7.68 (2H, m, ArH), 7.74-7.77 (4H, m, furylH/thienylH/2ArH),
MS (ESf) m/z 403.2 (M+l);
HPLCmethod i 98.1%/6.75 min.
By adapting the procedure in example 7, the compounds of Table 3 were prepared:
Table 3: Compounds prepared by the procedure of Example 7
Figure imgf000050_0001
Figure imgf000051_0001
(3 -Cyano-4-f uran- 8.00 411.3 2-yl-6-p-tolyl- method 1 (M+l) pyridin-2-yloxy)- phenyl- acetic acid
Figure imgf000052_0001
409.2
(M-I)
(3-Cyano-4-ethyl- Y 6.69 359.2 6-phenyl-pyridin- method 1 (M+l) 2-yloxy)-phenyl-
Figure imgf000052_0002
acetic acid
357.2
(M-I)
(3-Cyano-4- 7.35 373.3 isopropyl-6- method 1 (M+l) phenyl-pyridin-2-
Figure imgf000052_0003
yloxy)-phenyl- acetic acid
371.1
(M-I)
(3-Cyano-6- Y 7.49 413.3 phenyl-4-thiophen- method 1 (M+l) 2-yl-pyridin-2- yloxy)-phenyl-
Figure imgf000053_0001
acetic acid
411.2
(M-I)
(3-Cyano-4- Y 8.37 427.3 thiophen-2-yl-6~p- method 1 (M+l) tolyl-pyridin-2- yloxy)-phenyl-
Figure imgf000053_0002
acetic acid
425.1
(M-I)
(3-Cyano-4- Y 7.47 413.2 phenyl-6-thiophen- method 1 (M+l) 2-yl-pyridin-2- yloxy)-phenyl-
Figure imgf000053_0003
acetic acid
411.2
(M-I)
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Example 8
Preparation of 2-[3-Cyano-4-(2-furyl)-6-(2-thienyl)-2-pyridinyl]oxy-2-phenylacetic acid (Step C)
Figure imgf000058_0001
Acid (1 mmol) was dissolved/suspended in methanol (1 mL) with stirring. Aqueous sodium hydroxide solution (2.0 M, 1 mmol) (or aqueous tris solution (2.0 M, 1 mmol)) was added and the resulting mixture stirred for 10 min at room temperature. Volatiles were removed in vacuo and the residue dissolved in water (2 mL) filtered (porsity 4 sinter) and freeze dried for 2 d.
1H NMR (300 MHz, D2O) δ 5.95 (IH, s, CHPh), 6.55 (IH, dd, /=3.6, 1.8Hz, H4'), 7.07 (IH, app t, H4"), 7.28 (IH, d, J = 3.6 Hz, H3'), 7.44 (5H, m, ArH), 7.54 (IH, d, /= 5.1 Hz, H5"), 7.64 (3H, m, ArH); HPLCmethod i 100%/ 6.64 min.
By adapting the procedure described in Example 8, the compounds of Table 4 were prepared:
Table 4: Compounds prepared by the procedure of Example 8
Compound structure Compound name 1HL LC MS
(3-Cyano-4-furan-2- 6.64 yl-6-thiophen-2-yl- method 1 pyridin-2-yloxy)- phenyl-acetate2-
Figure imgf000059_0001
hydroxy-l,l-bis- hydroxymethyl-ethyl- ammonium;
Sodium; (3-cyano-4- Y phenyl-6-thiophen-2- yl-pyridin-2-yloxy)- phenyl-acetate
Sodium; (3-cyano-6- Y phenyl-4-thiophen-2- yl-pyridin-2-yloxy)- phenyl- acetate
Sodium; (3-cyano-4- Y thiophen-2-yl-6-p- tolyl-pyridin-2- yloxy)-phenyl-acetate
Figure imgf000059_0002
Compound structure Compound name 1H LC MS
Sodium; (3-cyano- Y 4,6-di-thiophen-2-yl- pyridin-2-yloxy)- phenyl-acetate
Sodium; [6-(4-bromo- Y 8.92 phenyl)-3 -cyano-4- method 1
(2,2-dimethyl-
[l,3]dioxolan-4-yl)- ρyridin-2-yloxy]-
Figure imgf000060_0001
phenyl-acetate
Sodium; [3-cyano-4- Y 6.83/7.09 459
(2,2-dimethyl- method 1 (M+l)
[ 1 ,3]dioxolan-4-yl)-6- thiophen-2-yl-pyridin-
Figure imgf000060_0002
2-yloxy]-phenyl- acetate
Sodium; (3-cyano-4- Y 7.37 401 isopropyl-6-thiophen- method 1 (M+l) 2-yl-pyridin-2-yloxy)- phenyl-acetate
Figure imgf000060_0003
Sodium; [3-cyano-4- Y 7.26/7.55 (2,2-dimethyl- method 1 [l,3]dioxolan-4-yl)-6- phenyl-pyridin-2-
Figure imgf000060_0004
yloxy] -phenyl-acetate
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Compound structure Compound name 1H LC MS
Sodium; [4-(4- 0.92 methoxy-phenyl)-6- method 2 thiophen-2-yl-pyridin- 2-yloxy] -phenyl- acetate
Sodium; (3-cyano-4- 2.78 furan-3-yl-6- method 2 thiophen-2-yl-pyridin-
2-yloxy)-phenyl-
Figure imgf000066_0001
acetate
Sodium; (3-cyano-4- 2.64 furan-3 -yl-6-thiazol- method 2 2-yl-pyridin-2-yloxy)- phenyl-acetate
Figure imgf000066_0002
Sodium; (3-cyano-4- 2.68 furan-2-yl-6-thiazol- method 2 2-yl-pyridin-2-yloxy)- phenyl-acetate
Figure imgf000066_0003
Sodium; [4-(4- Y 1.65 434 methoxy-phenyl)-6- method 2 (M+l) thiophen-2-yl-pyridin- 2-ylsulf anyl] -phenyl- 456 acetate
Figure imgf000066_0004
(M+23)
Figure imgf000067_0001
Compound structure Compound name 1H LC MS
Sodium; [3-cyano-4- 7.09
(4-methoxy-phenyl)- method 1
6-thiophen-2-yl- pyridin-2-yloxy]- phenyl-acetate
Sodium; (3-cyano-4- 2.86 furan-2-yl-6-p-tolyl- method 2 pyridin-2-yloxy)- phenyl-acetate
Sodium; (3-cyano-6- 2.71 phenyl-4- method 2 trifluoromethyl-
Figure imgf000068_0001
pyridin-2-ylsulfanyl)-
Na phenyl-acetate
Sodium; (3-cyano- 2.81 4,6-diphenyl-pyridin- method 2 2-ylsulfanyl)-phenyl- acetate
Figure imgf000068_0002
Na Compound structure Compound name 1B. LC MS
Sodium; [3-cyano-4- 2.73
(4-fluoro-phenyl)-6- method 2 thiophen-2-yl-pyridin-
2-yloxy]-phenyl- acetate
Sodium; (3-cyano- 2.53
4,6-diphenyl-pyridin- method 2
2-ylsulfanyl)-acetate
Sodium; (4-furan-2- 2.63 yl-6-thiophen-2-yl- method 2 pyridin-2-yloxy)- phenyl-acetate
Figure imgf000069_0001
Sodium; (3-cyano-4- 2.42 ethyl-6-phenyl- method 2 pyridin-2-yloxy)- phenyl-acetate
Figure imgf000069_0002
Example 9 Biological testing
Compounds of the present invention were tested for biological activity using the assay techniques below: 3'processing/strand transfer combined assay :
A combined 3 '-processing/strand transfer assay procedure similar to that published (Ovenden et al. Phytochemistry. 2004 Dec;65(24):3255-9.) was used. This assay was adapted to a 96 well plate format. Briefly, 400ng of the compound to be tested is incubated with 3OnM substrate DNA, consisting of annealed U5 LTR sequence oligonucleotides tagged with
Digoxigenin (DIG; 5'-ACTGCTAGAGATTTTCCACACTGACTAAAAGGGTC-DIG-S') or biotin (5'-BiO-GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT-S') so that each substrate has either a DIG or Bio tag on opposite strands. Reactions are carried out for 2hrs at 37°C, products generated as a result of 3'processing and strand transfer activity are bound to streptavidin plates and detected with using anti-DIG-alkaline phosphatase conjugate and p- nitro phenyl phosphate substrate.
Strand transfer specific assay:
The strand transfer specific assay is of similar format to that of the 3'processing/strand transfer combined assay except that it uses a biotinylated substrate that represents a pre- processed LTR end (5'-BiO-GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCA-S').
Inhibition of HIV replication:
Cells are seeded into 96 well microtitre plates at 50,000 cells per 50ul per well in RF- 10 containing 2μg/ mL polybrene (RF- 10/2). Compounds are prepared to 4 x final concentration in RF-10/2, and 30μl added to cells. Virus (40μl in RF-10/2 containing 1600 pfu) is added to each well or 40μl RF-10/2 for negative controls and for assaying compound cytotoxicity.
After 24 hrs, an additional 90ul of media or media containing 1 x compound is added to each well. At 4 days post infection, lOOμl of media is removed from each well and replaced with lOOμl of fresh media with or without compound. Forty eight hours later supernatants are harvested and levels of extracellular p24 determined. Supernatants are diluted 1 in 10,000 and p24 levels assayed using the Vironostika p24 assay kit. EC50 is calculated as the concentration required to inhibit HIV p24 production to 50% that of no drug controls. The results of the assays for four compounds of the present invention are presented below in which:
• IC50 (3'-ST) represents the assay results for the 3 'processing/strand transfer combined assay;
• IC50 (ST) represents the assay results for the strand transfer specific assay; and
• EC50 represents the results for the inhibition of HIV replication.
Table 5 depicts the "scoring system" used in the assays.
Table 5: Assay scoring system
Figure imgf000071_0001
Assay results
Figure imgf000072_0001
IC50 (3'-ST) ++
IC50 (3'-ST) +++
IC50 (ST) + IC50 (ST) +++
EC1
EC50 ++ 50
Figure imgf000072_0002
Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before the priority date of each claim of this application.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. A method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000074_0001
X is selected from -O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -O-, and -NR6-;
each R6 is independently selected from H and C1-3alkyl;
R1, R2 and R4 are each independently selected from the group consisting of hydrogen, C6-1oaryl, C6-1oarylC1-3alkyl, heterocyclyl, hetereoaryl, C1-1OaIlCyI and C3-1ocycloalkyl, -NR7R8, -Sd-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, and CO2R9;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-10alkyl, C6-10arylC1-3alkyl and Ce-^aryl; and
R5 is selected from the group consisting of hydrogen, Cnoalkyl, and C2-1oalkenyl.
2. A method according to claim 1 wherein R1 is selected from C6_10aryl and heteroaryl.
3. A method according to claim 1 or claim 2 wherein R2 is selected from C6-1oaryl, heteroaryl, heterocyclyl and C3-6cycloalkyl.
4. A method according to any one of claim 1 to 3 wherein R3 is selected from hydrogen and cyano.
5. A method according to any one of claims 1 to 4 wherein R4 is C6aryl.
6. A method according to any one of claims 1 to 5 wherein R5 is selected from hydrogen and C2-3alkenyl.
7. A method according to claim 6 wherein R5 is allyl.
8. A method according to claim 1 wherein the compound of formula I is selected from the group consisting of:
Figure imgf000075_0001
9. A method according to any one of claims 1 to 8 wherein the viral infection is a HIV infection.
10. A compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000076_0001
X is selected from -O-, -S-, -S(O)-, -S(O2)-, and -NR6-;
Y is selected from -O-, and -NR6-;
each R6 is independently selected from H and C1-3alkyl;
R1, R2 and R4 are each independently selected from the group consisting of hydrogen, Cβ-ioaryl, C6-1oarylCi-3alkyl, heterocyclyl, hetereoaryl, C1-1OaIkVl and C3-1ocycloalkyl, -NR7R8, -SCi-Cioalkyl;
R3 is selected from the group consisting of hydrogen, cyano, -C(O)NR7R8, -CH2NR7R8, and CO2R9;
R7, R8 and R9 are each independently selected from the group consisting of hydrogen, C1-1OaDCyI,
Figure imgf000076_0002
and C6-loaryl; and
R5 is selected from the group consisting of hydrogen, C1-1QaIkVl, and C2-1oalkenyl.
11. A compound according to claim 10 wherein R1 is selected from C6-1oaryl and heteroaryl.
12. A compound according to claim 10 or claim 11 wherein R2 is selected from Cβ-ioaryl, heteroaryl, heterocyclyl and C3-6cycloalkyl.
13. A compound according to any one of claims 10 to 12 wherein R3 is selected from hydrogen and cyano.
14. A compound according to any one of claims 10 to 13 wherein R4 is C6aryl.
15. A compound according to any one of claims 10 to 14 wherein R5 is selected from hydrogen and C2-3alkenyl.
16. A compound according to claim 15 wherein R5 is allyl.
17. A compound of formula I according to claim 10 selected from the group consisting of:
Figure imgf000077_0001
18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, diluent or excipient.
PCT/AU2007/000560 2006-04-28 2007-04-30 Integrase inhibitors - 2 WO2007124545A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2006902228A AU2006902228A0 (en) 2006-04-28 Integrase inhibitor (2)
AU2006902228 2006-04-28

Publications (1)

Publication Number Publication Date
WO2007124545A1 true WO2007124545A1 (en) 2007-11-08

Family

ID=38654993

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2007/000560 WO2007124545A1 (en) 2006-04-28 2007-04-30 Integrase inhibitors - 2

Country Status (1)

Country Link
WO (1) WO2007124545A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087212A3 (en) * 2008-01-11 2009-09-24 Novartis Ag Pyridine derivatives
WO2011133727A2 (en) 2010-04-23 2011-10-27 Kineta, Inc. Anti-viral compounds
US9844218B2 (en) 2013-06-13 2017-12-19 Monsanto Technology Llc Acetyl-CoA carboxylase modulators
US10207995B2 (en) 2013-06-13 2019-02-19 Monsanto Technology Llc Acetyl CoA carboxylase modulators
CN109771422A (en) * 2019-03-15 2019-05-21 中国药科大学 Medicinal use of 2-(pyridine-2-thio)acetic acid in anti-mycobacterium tuberculosis infection

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD271112A1 (en) * 1988-03-01 1989-08-23 Univ Leipzig PROCESS FOR PREPARING NEW 2-ALKYLTHIO-6-METHYL-4-PYRIDYL-PYRIDINE-3-CARBONITRILE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD271112A1 (en) * 1988-03-01 1989-08-23 Univ Leipzig PROCESS FOR PREPARING NEW 2-ALKYLTHIO-6-METHYL-4-PYRIDYL-PYRIDINE-3-CARBONITRILE

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
ABDEL MONEAM M.I. ET AL.: "Synthesis of pyridothienopyridines and arylazothienopyridines", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 178, no. 12, 2003, pages 2639 - 2651 *
ABDEL-RAHMAN A.E. ET AL.: "Fluorine-containing heterocycles: Part II. Synthesis and reactions of new thieno[2,3-b]pyridine derivatives bearing trifluoromethyl group", JOURNAL OF CHEMICAL RESEARCH, no. 7, 2005, pages 461 - 468 *
AMR A.-G.E. ET AL.: "Synthesis and Reactions of Some Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives with a Thiophene Ring as Analgesic, Anticonvulsant, and Antiparkinsonian Agents", MONATSHEFTE FOR CHEMIE, vol. 134, no. 10, 2003, pages 1395 - 1409 *
ATTABY F.A. ET AL.: "Synthesis and antimicrobial evaluation of several new pyridine, thienopyridine and pyridothienopyrazole derivatives", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 149, 1999, pages 49 - 64, XP008049443 *
ATTABY F.A. ET AL.: "Synthesis of 2-thioxohydropyridine-3-carbonitrile, 2-alkylthiopyridine, thienopyridine, pyrazolopyridine derivatives and their theoretical calculations", JOURNAL OF THE CHINESE CHEMICAL SOCIETY (TAIPEI, TAIWAN), vol. 49, no. 4, 2002, pages 561 - 569 *
ATTABY F.A.: "Reactions of styryl thienyl ketone, styryl furyl ketone with thiocyanoacetamide: synthesis of several new pyridines, thieno[2,3-b]pyridines, pyrido[2',3':4,5]thieno[3,2-c]pyridazines and pyrido[3',2:'4,5]thieno[3,2-d]pyrimidinone derivatives", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 139, 1998, pages 1 - 12 *
ATTIA A. ET AL.: "Synthesis of some furopyridine derivatives", EGYPTIAN JOURNAL OF CHEMISTRY, vol. 28, no. 5, 1985, pages 427 - 432 *
BAKHITE E. ET AL.: "Synthesis and reactions of some new heterocyclic compounds containing the thienylthieno[2,3-b]pyridine moiety", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 179, no. 10, 2004, pages 1983 - 2006 *
CHANDRA S.R. ET AL.: "Fluoro-organics: trifluoromethyl group-induced O-alkylation of pyridin-2-ones", JOURNAL OF FLUORINE CHEMISTRY, vol. 78, no. 1, 1996, pages 21 - 25 *
DAVE C.G. ET AL.: "Synthesis and reactions of 2-carbethoxy-3-aminothieno[2,3-b]pyridines", INDIAN JOURNAL OF CHEMISTRY, vol. 31B, no. 8, 1992, pages 492 - 494 *
DYACHENKO V.D. ET AL.: "Unexpected formation of 4-aryl-3-cyano-6-phenylpyridine-2(1H)-thiones from the reaction of arylmethylenecyanothioacetamides with benzoyl-1,1,1-trifluoroacetone", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 41, no. 12, 2005, pages 1499 - 1506, XP019219973 *
ERIAN A.W. ET AL.: "Electrolytic partial fluorination of organic compounds. 13. Selective anodic a-fluorination of nitrogen-containing heterocyclic sulfides and its application to the synthesis of fluorinated fused heterocycles", TETRAHEDRON LETTERS, vol. 35, no. 39, 1994, pages 7245 - 7248 *
ERIAN A.W. ET AL.: "Electrolytic Partial Fluorination of Organic Compounds. 19. A Novel Synthesis of Fluorothieno[2,3-b]pyridines Using Anodic Fluorination of Heterocyclic Sulfides as a Key Step", JOURNAL OF ORGANIC CHEMISTRY, vol. 60, no. 23, 1995, pages 7654 - 7659 *
ESSAWY A. ET AL.: "Synthesis and some reactions of 3-cyano-4-phenyl-6-[2'-methoxynaphthalenyl)]-2-pyridone", REVUE ROUMAINE DE CHIMIE, vol. 26, no. 8, 1981, pages 1141 - 1148 *
GHORAB M.-M. ET AL.: "Synthesis of novel heterocyclic compounds for antitumor and radioprotective activities", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 134/135, 1998, pages 447 - 462 *
HASSAN K.M. ET AL.: "Synthesis and reactions of some thienopyridine derivatives", PHOSPHORUS, SULFUR AND SILICON AND RELATED ELEMENTS, vol. 47, no. 1-2, 1990, pages 181 - 189 *
HASSANIEN A.Z.A. ET AL.: "Synthesis of some new pyridines, thienopyridines and pyrido[2,3:4',5']thieno[3',2'-d]pyrimidin-8-ones from 2-acetylbenzoimidazole", CROATICA CHEMICA ACTA, vol. 78, no. 1, 2005, pages 63 - 70 *
KRAUZE A. ET AL.: "Derivatives of 3-cyano-6-phenyl-4-(3'-pyridyl)-pyrimidine-2(1H)-thione and their neurotropic activity", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 34, no. 4, 1999, pages 301 - 310, XP004178573 *
LIN C.-F. ET AL.: "Cathylation of 4,6-dimethyl-2-oxopyridine-3-carbonitrile derivatives leading to the synthesis of furo[2,3-b:4,5-b']dipyridines and a novel tricyclic furo[2,3,4-ij][2,7]naphthyridine", HETEROCYCLES, vol. 53, no. 1, 2000, pages 15 - 26 *
NARSAIAH B. ET AL.: "Synthesis of novel 2,7-disubstituted-3-amino-9-trifluoromethyl-4-oxo-4H-pyrido[3',2':4,5]-furo-[3,2-d]-(1,3)-pyrimidines", JOURNAL OF FLUORINE CHEMISTRY, vol. 69, no. 2, 1994, pages 139 - 143, XP002446226 *
SAYED G.H. ET AL.: "Studies on the condensation products of 1,3-diaryl-2-propen-1-one with ethyl cyanoacetate", JOURNAL OF THE CHEMICAL SOCIETY OF PAKISTAN, vol. 5, no. 3, 1983, pages 195 - 199 *
SHESTOPALOV A.M. ET AL.: "Cyclization of nitriles. IX. Syntheses based on 2-aryl-3-aroyl-1,1-dicyanopropanes", JOURNAL OF ORGANIC CHEMISTRY OF THE USSR, vol. 21, 1985, pages 1382 - 1401 *
SHIBA S.A. ET AL.: "N- vs. O-(S-) PTC alkylation of 3-cyano-4,6-dimethyl-2-oxo(thioxo-1,2-dihydropyridine", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 158, 2000, pages 91 - 95 *
WAGNER G. ET AL.: "Synthesis of new primary, secondary and tertiary 3-aminoethieno[2,3-b]pyridine-2-carboxamides on different ways", PHARMAZIE, vol. 45, no. 2, 1990, pages 102 - 109, XP001154945 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009203681B2 (en) * 2008-01-11 2012-08-16 Novartis Ag Pyridine derivatives
JP2011509277A (en) * 2008-01-11 2011-03-24 ノバルティス アーゲー Pyridine derivatives
WO2009087212A3 (en) * 2008-01-11 2009-09-24 Novartis Ag Pyridine derivatives
US8343966B2 (en) 2008-01-11 2013-01-01 Novartis Ag Organic compounds
EP2560657A4 (en) * 2010-04-23 2014-02-19 Kineta Inc ANTIVIRAL COMPOUNDS
US9301952B2 (en) 2010-04-23 2016-04-05 Kineta, Inc. Diarylpyridine anti-viral compounds
US20130039944A1 (en) * 2010-04-23 2013-02-14 Kineta, Inc. Anti-Viral Compounds
JP2013525367A (en) * 2010-04-23 2013-06-20 キネタ・インコーポレイテツド Antiviral compounds
WO2011133727A2 (en) 2010-04-23 2011-10-27 Kineta, Inc. Anti-viral compounds
AU2011242688B2 (en) * 2010-04-23 2015-01-22 Kineta, Inc. Anti-viral compounds
EP2977085A1 (en) * 2010-04-23 2016-01-27 Kineta, Inc. Diarylpyridine anti-viral compounds
WO2011133727A3 (en) * 2010-04-23 2012-03-08 Kineta, Inc. Anti-viral compounds
US9844218B2 (en) 2013-06-13 2017-12-19 Monsanto Technology Llc Acetyl-CoA carboxylase modulators
US10207995B2 (en) 2013-06-13 2019-02-19 Monsanto Technology Llc Acetyl CoA carboxylase modulators
US10548313B2 (en) 2013-06-13 2020-02-04 Monsanto Technology Llc Acetyl-CoA carboxylase modulators
US10995070B2 (en) 2013-06-13 2021-05-04 Monsanto Technology Llc Acetyl-CoA carboxylase modulators
US11375716B2 (en) 2013-06-13 2022-07-05 Monsanto Technology Llc Acetyl-CoA carboxylase modulators
CN109771422A (en) * 2019-03-15 2019-05-21 中国药科大学 Medicinal use of 2-(pyridine-2-thio)acetic acid in anti-mycobacterium tuberculosis infection

Similar Documents

Publication Publication Date Title
KR102666406B1 (en) Bicyclic derivatives
AU740318B2 (en) Dihydropyrimidines
EP1869037B1 (en) Heterobicylic inhibitors of hvc
AU2002230618B2 (en) Heterocyclic ether substituted imidazoquinolines
EP2019827A1 (en) Integrase inhibitors 3
CA2262692C (en) Substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives
EP1444228B1 (en) Substituted heteroarylalkanoic acids and their use as aldose reductase inhibitors
JP4287649B2 (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
JP2023103379A (en) Short-chain dehydrogenase activity inhibitors for treating fibrosis
US7696223B2 (en) Pyrrolo- and Thiazolo-pyridine compounds, and methods of use thereof
CA2409743C (en) Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors
US20030229090A1 (en) 1,6 Naphthyridines useful as inhibitors of SYK kinase
JP5743901B2 (en) Triazolopyridine derivatives as phosphodiesterase inhibitors for the treatment of skin diseases
CZ287613B6 (en) Pyrazolo- and pyrrolopyridines and pharmaceutical preparations based thereon
WO2016148114A1 (en) Compound capable of inhibiting oxidative stress-induced neuronal cell death
KR20100031610A (en) Triazolo[1,5-a]quinolines as adenosine a3 receptor ligands
WO2007124545A1 (en) Integrase inhibitors - 2
EP2247601A1 (en) Thiazopyrimidinones and uses thereof
WO2007124544A1 (en) Integrase inhibitors - 1
EP4079724A1 (en) Fused ring compound and application thereof
EP1252163A2 (en) 4-pyridyl-and 2,4-pyrimidinyl-substituted pyrrole derivatives and their use in pharmacy
JP2018039733A (en) Novel heterocyclic derivative
JP2002544272A (en) Substituted 3-pyridyl-4-arylpyrroles and related treatments and prophylaxis
CN116375728B (en) Thiophene pyrrolotriazinone compound and application thereof
TW202328072A (en) Ahr agonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07718807

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07718807

Country of ref document: EP

Kind code of ref document: A1